1. Field of the Invention
The present invention generally relates to the fields of molecular biology and medicine. More particularly, it concerns the discovery of compounds that inhibit Wnt-mediated signal transduction pathways, including the Wnt/β-catenin pathway.
2. Description of Related Art
The secreted Wnt signalling proteins are deployed in almost all aspects of embryonic development in vertebrates (Clevers, 2006). In post-embryonic animals, their functions are essential to homeostatic tissue renewal and regeneration (Reya and Clevers, 2005). Similar to that of several other signal transduction pathways that have been shown to be important to cell fate decision-making, activity of the Wnt/β-catenin pathway maintains transcriptional programs that enable stem cells to retain their multi-potency (Cole et al., 2008; Van der Flier et al., 2007). Inability to sustain these transcription programs, perhaps through loss of members of the TCF/LEF family of transcriptional effectors or the β-catenin transcriptional co-activator, results in compromised ability of stem cells to self-renew (Cole et al., 2008; Fevr et al., 2007; Korinek et al., 1998; Muncan et al., 2007).
Pathological states that may arise from altered stem cell function, such as degenerative diseases and cancer, are frequently associated with changes in Wnt/β-catenin pathway activity. Indeed, hyperactivation of the Wnt/β-catenin pathway is thought to induce premature senescence of stem cells and age-related loss of stem cell function (Brack et al., 2007; Liu et al., 2007). In cancer, hyperactivation of the Wnt/β-catenin pathway, often in conjunction with mutations in other cell growth regulatory genes, can lead to aberrant cell growth (Reya and Clevers, 2005). Notably, 90% of colorectal cancers are initiated by the loss of the adenomatosis polyposis coli (APC) gene, a major suppressor of the Wnt/β-catenin pathway (Kinzler and Vogelstein, 1996; Sjoblom et al., 2006). Less frequently, loss of extracellular inhibitors that normally suppress Wnt protein function may give rise to Wnt ligand-dependent tumors (Polakis, 2007). More recently, Wnt-mediated cellular responses that are not dependent upon β-catenin (so called “non-canonical pathways” have also been shown play important roles in cancer (Veeman et al., 2003).
Accordingly, identification of methods and compounds that modulate the Wnt-dependent cellular responses may offer an avenue for therapeutic treatment of diseases associated with aberrant activity of these pathways.